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The Journal of Neuroscience, May 15, 2001, 21(10):3409-3418

Loss of the Major GABA_A Receptor Subtype in the Brain Is Not Lethal in Mice

Cyrille Sur, Keith A. Wafford, David S. Reynolds, Karen L. Hadingham, Frances Bromidge, Alison Macaulay, Neil Collinson, Gillian O'Meara, Owain Howell, Richard Newman, Janice Myers, John R. Atack, Gerard R. Dawson, Ruth M. McKernan, Paul J. Whiting, and Thomas W. Rosahl

Neuroscience Research Center, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, CM20 2QR, United Kingdom

The 122 is the most abundant subtype of the GABA_A receptor and is localized in many regions of the brain. To gain more insight into the role of this receptor subtype in the modulation of inhibitory neurotransmission, we generated mice lacking either the 1 or 2 subunit. In agreement with the reported abundance of this subtype, >50% of total GABA_A receptors are lost in both 1/ and 2/ mice. Surprisingly, homozygotes of both mouse lines are viable, fertile, and show no spontaneous seizures. Initially half of the 1/ mice died prenatally or perinatally, but they exhibited a lower mortality rate in subsequent generations, suggesting some phenotypic drift and adaptive changes. Both adult 1/ and 2/ mice demonstrate normal performances on the rotarod, but 2/ mice displayed increased locomotor activity. Purkinje cells of the cerebellum primarily express 122 receptors, and in electrophysiological recordings from 1/ mice GABA currents in these neurons are dramatically reduced, and residual currents have a benzodiazepine pharmacology characteristic of 2- or 3-containing receptors. In contrast, the cerebellar Purkinje neurons from 2/ mice have only a relatively small reduction of GABA currents. In 2/ mice expression levels of all six  subunits are reduced by ~50%, suggesting that the 2 subunit can coassemble with  subunits other than just 1. Our data confirm that 122 is the major GABA_A receptor subtype in the murine brain and demonstrate that, surprisingly, the loss of this receptor subtype is not lethal.

Key words: GABA_A receptor; mouse; cerebellum; radioligand; benzodiazepine; inhibitory current; locomotor activity; rotarod

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21103409-10$05.00/0

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